Pyrazolobenzodiazepines

ABSTRACT

Disclosed are novel pyrazolobenzodiazepines having the formula 
                 
 
     These compounds are useful in the preparation of the pyrazolobenzodiazepines of formula I, which are useful in the treatment and control of solid tumors.

This application is a Divisional application of Ser. No. 09/548,091,filed Apr. 12, 2000 now U.S. Pat. No. 6,440,959, which claims priorityof Provisional application Serial No. 60/130,370, filed Apr. 21, 1999.

FIELD OF THE INVENTION

The present invention is directed to novel pyrazolobenzodiazepines whichinhibit cyclin-dependent kinases (CDKs), in particular CDK2. Thesecompounds and their pharmaceutically acceptable salts, and prodrugs ofsaid compounds, are anti-proliferative agents useful in the treatment orcontrol of cell proliferative disorders, in particular cancer. Theinvention is also directed to pharmaceutical compositions containingsuch compounds, and to methods for the treatment and/or prevention ofcancer, particularly in the treatment or control of solid tumors. Thecompounds of the invention are especially useful in the treatment orcontrol of breast, colon, lung and prostate tumors. The invention isalso directed to intermediates useful in the preparation of the aboveanti-proliferative agents.

BACKGROUND OF THE INVENTION

Uncontrolled cell proliferation is the hallmark of cancer. Canceroustumor cells typically have some form of damage to the genes thatdirectly or indirectly regulate the cell-division cycle.

Cyclin-dependent kinases (CDKs) are enzymes which are critical to cellcycle control. See, e.g., Coleman et al., “Chemical Inhibitors ofCyclin-dependent Kinases,” Annual Reports in Medicinal Chemistry, vol.32, 1997, pp. 171-179. These enzymes regulate the transitions betweenthe different phases of the cell cycle, such as the progression from theG₁ phase to the S phase (the period of active DNA synthesis), or theprogression from the G₂ phase to the M phase, in which active mitosisand cell-division occurs. See, e.g., the articles on this subjectappearing in Science, vol. 274, Dec. 6, 1996, pp 1643-1677.

CDKs are composed of a catalytic CDK subunit and a regulatory cyclinsubunit. The cyclin subunit is the key regulator of CDK activity, witheach CDK interacting with a specific subset of cyclins: e.g. cyclin A(CDK1, CDK 2). The different kinase/cyclin pairs regulate progressionthrough specific stages of the cell cycle. See, e.g., Coleman, supra.

Aberrations in the cell cycle control system have been implicated in theuncontrolled growth of cancerous cells. See, e.g., Kamb, “Cell-CycleRegulators and Cancer,” Trends in Genetics, vol. 11, 1995, pp.136-140;and Coleman, supra. In addition, changes in the expression of or in thegenes encoding CDK's or their regulators have been observed in a numberof tumors. See, e.g., Webster, “The Therapeutic Potential of Targetingthe Cell Cycle,” Exp. Opin. Invest. Drugs, Vol. 7, pp. 865-887 (1998),and references cited therein. Thus, there is an extensive body ofliterature validating the use of compounds inhibiting CDKs asanti-proliferative therapeutic agents. See, e.g. U.S. Pat. No. 5,621,082to Xiong et al; EP 0 666 270 A2; WO 97/16447; and the references citedin Coleman, supra, in particular reference no. 10. Thus, it is desirableto identify chemical inhibitors of CDK kinase activity.

It is particularly desirable to identify small molecule compounds thatmay be readily synthesized and are effective in inhibiting one or moreCDKs or CDK/cyclin complexes, for treating one or more types of tumors.

Several classes of compounds that inhibit cyclin-dependent kinases havebeen and are being investigated as therapeutic agents. These are, forexample, as follows:

-   Analogs of Flavopiridol:-   U.S. Pat. No. 5,733,920 (Mitotix)-   WO 98/1344 (Bristol-Myers Squibb)-   WO 97/42949 (Bristol-Meyers Squibb)-   Purine Derivatives:-   WO 98/05335 (CV Therapeutics)-   WO 97/20842 (CNRS)-   Acridones and Benzothiadiazines:-   WO 98/49146 A2 (US Dept. of Health and Human Services)-   Antisense-   U.S. Pat. No. 5,821,234 (Stanford University).

Furthermore, certain N,N-substituted dihydropyrazolobenzodiazepines havebeen disclosed in an article discussing CNS-acting compounds. See, M. A.Berghot, Arch. Pharm. 325:285-289 (1992).

There continues to be a need for easily synthesized, small moleculecompounds for the treatment of one or more types of tumors, inparticular through regulation of CDKs. It is thus an object of thisinvention to provide such compounds and compositions containing suchcompounds.

SUMMARY OF THE INVENTION

The present invention relates to pyrazolobenzodiazepines capable ofinhibiting the activity of one or more CDKs, in particular CDK2. Suchcompounds are useful for the treatment of cancer, in particular solidtumors. In particular the compounds of the present invention areespecially useful in the treatment or control of breast, colon, lung andprostate tumors. The invention is also directed to intermediatecompounds useful in the preparation of the above-mentionedpyrazolobenzodiazepines.

The compounds of the present invention are compounds of formula I below

and prodrugs and metabolites of the foregoing compounds, as well aspharmaceutically acceptable salts of each of the foregoing compounds,wherein

-   -   R¹ is selected from the group consisting of        -   —H,        -   —NO₂,        -   —CN,        -   -halogen,        -   -lower alkyl which is straight-chained and which optionally            may be substituted by the group consisting of —OH and            halogen,        -   —OR⁵,        -   —R⁶OR⁷,        -   COOR⁷,        -   CONR⁸R⁹ (a.k.a. carboxamide),        -   NR¹⁰R¹¹,        -   —NHCOR¹², and        -   —NHSO₂R¹³;    -   R² and R⁴ are each independently selected from the group        consisting of        -   —H,        -   halogen,        -   —NO₂,        -   —CF₃, and        -   -straight chained lower alkyl;    -   R³ is selected from the group consisting of        -   —H,        -   -lower alkyl which optionally may be substituted by —OH,        -   —OR⁹, F, and aryl,        -   -cycloalkyl,        -   -aryl,        -   heterocycle,        -   heteroaryl,        -   COOR⁷        -   —CN,        -   -alkenyl,        -   —CONR⁸R⁹, and        -   -alkynyl;    -   R⁵ is selected from lower alkyl which optionally may be        substituted by halogen;    -   R⁶ is selected from lower alkyl;    -   R⁷ is selected from the group consisting of —H and lower alkyl;    -   R⁸ and R⁹ are each independently selected from the group        consisting of —H and -lower alkyl which itself optionally may be        substituted by —OH and —NH₂; alternatively, R⁸ and R⁹ may form a        5- or 6-membered heterocycle which optionally may be substituted        by the group consisting of —OH, —NH₂, and lower alkyl;    -   R¹⁰, R¹¹ and R¹² are each independently selected from the group        consisting of —H and lower alkyl;    -   R¹³ is selected from the group consisting of lower alkyl which        optionally may be substituted by the group consisting of halogen        and —NR¹⁴R¹⁵; and    -   R¹⁴ and R¹⁵ are each independently selected from the group        consisting of —H and lower alkyl which optionally may be        substituted Halogen, or alternatively, —NR¹⁴R¹⁵ is a        heterocycle.

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of any one or more of theabove-described compounds, or a pharmaceutically acceptable salt orprodrug thereof, and a pharmaceutically acceptable carrier or excipient.

The present invention is also directed to a method for treating solidtumors, in particular breast, colon, lung and prostate tumors, morespecifically breast and colon tumors, by administering to a humanpatient in need of such therapy an effective amount of a compound offormula 1, its salts or prodrugs.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms shall have the followingdefinitions.

“Aryl” means an aromatic group having 5 to 10 atoms and consisting of 1or 2 rings. Examples of aryl groups include phenyl and 1- or 2-naphthyl.

“Alkenyl” means a straight-chain or branched, substituted orunsubstituted, aliphatic unsaturated hydrocarbon having 2 to 6,preferably 2 to 4, carbon atoms and containing double bonds. Typicalalkenyl groups include ethylene, propylene, isopropylene, butylene andthe like. Preferred alkenyl groups are straight-chained.

“Alkynyl” means a straight-chain or branched, substituted orunsubstituted, aliphatic unsaturated hydrocarbon having 2 to 6,preferably 2 to 4, carbon atoms and containing triple bonds. Typicalalkynyl groups include acetylene and the like. Preferred alkynyl groupsare straight-chained.

“Cycloalkyl” means a non-aromatic, partially or completely saturatedcyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

“Effective Amount” means an amount of at least one compound of FormulaI, or a pharmaceutically acceptable salt, prodrug or metabolite thereof,that significantly inhibits proliferation of a tumor cell, includinghuman tumor cell lines.

“Halogen” means fluorine, chlorine, bromine or iodine. Preferredhalogens are fluorine and chlorine.

“Heteroaryl” groups are aromatic groups having 5 to 10 atoms, one or 2rings, and containing one or more hetero atoms. Examples of heteroarylgroups are 2-, 3- or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl,quinolyl, pyrrolyl, and imidazolyl.

“Hetero atom” means an atom selected from N, O and S.

“Heterocycle” means a 3- to 10-membered non-aromatic, partially orcompletely saturated hydrocarbon group, such as tetrahydroquinolyl,which contains one or two rings and at least one hetero atom.

“IC₅₀” refers to the concentration of a particularpyrazolobenzodiazepine required to inhibit 50% of a specific measuredactivity. IC₅₀ can be measured, inter alia, as is described in Example4, infra.

“Lower Alkyl” denotes a straight-chain or branched, substituted orunsubstituted, saturated aliphatic hydrocarbon having 1 to 6, preferably1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like.

“Pharmaceutically acceptable salt” refers to conventional acid-additionsalts or base-addition salts which retain the biological effectivenessand properties of the compounds of formula I and are formed fromsuitable non-toxic organic or inorganic acids or organic or inorganicbases. Sample acid-addition salts include those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluenesulfonic acid, salicylicacid, methanesulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, and the like. Samplebase-addition salts include those derived from ammonium, potassium,sodium and, quaternary ammonium hydroxides, such as for example,tetramethylammonium hydroxide.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, prodrug, etc., means pharmacologically acceptableand substantially non-toxic to the subject to which the particularcompound is administered.

“Pharmaceutically active metabolite” means a metabolic product of acompound of formula I which is pharmaceutically acceptable andeffective.

“Prodrug” refers to a compound that may be converted under physiologicalconditions or by solvolysis to any of the compounds of formula I or to apharmaceutically acceptable salt of a compound of formula I. A prodrugmay be inactive when administered to a subject but is converted in vivoto an active compound of formula I.

“Substituted,” as in substituted alkyl, means that the substitution canoccur at one or more positions and, unless otherwise indicated, that thesubstituents at each substitution site are independently selected fromthe specified options.

The Compounds

In one embodiment, the current invention is directed to compounds havingthe formula:

and prodrugs and pharmaceutically active metabolites of compounds offormula I, and the pharmaceutically acceptable salts of the foregoingcompounds, wherein R¹ through R¹⁵ are as defined above.

In a preferred embodiment of the compounds of formula I, R¹ is on the 7or 8 position and is selected from the group consisting of —H, —NO₂,—CN, —Halogen and unsubstituted lower alkyl. Preferred lower alkyls aremethyl and ethyl.

In another preferred embodiment of the compounds of formula I, R² is onthe 2′ position and is selected from the group consisting of —H and—Halogen.

In another preferred embodiment of the compounds of formula I, R³ isselected from the group consisting of unsubstituted lower alkyl,cycloalkyl, heterocycle, and heteroaryl. Preferred lower alkyl groupsare methyl and ethyl. Preferred cycloalkyl groups are unsubstitutedC₃-C₅.

In another preferred embodiment of the compounds of formula I, R⁴ is atthe 4′ position and is selected from the group consisting of —H and—Halogen, most preferably R⁴ is H.

In another preferred embodiment of the compounds of formula I, R⁵ and R⁶are independently selected from methyl or ethyl, each of whichoptionally may be substituted by halogen. More preferably, R⁵ istrifluoromethyl.

In another preferred embodiment of the compounds of formula I, R⁷ isselected from the group consisting of —H, methyl and ethyl.

In another preferred embodiment of the compounds of formula I, R⁸ and R⁹are each independently selected from —H, methyl, ethyl and hydroxyethyl.When R⁸ and R⁹ form a heterocycle, preferred heterocycle groups are6-membered, unsubstituted, groups that most preferably include twoheteroatoms. Most preferred heteroatoms are selected from O and N.

In another preferred embodiment of the compounds of formula I, R¹⁰, R¹¹,and R¹² are each independently selected from the group consisting of —H,methyl and ethyl.

In another preferred embodiment of the compounds of formula I, R¹³ islower alkyl which optionally may be substituted by halogen, mostpreferably R¹³ is methyl, ethyl, or trifluoromethyl.

In another preferred embodiment of the compounds of formula I, R¹⁴ andR¹⁵ are each independently selected from H, methyl, ethyl andheterocycle. Preferred heterocycles are 3-7 membered rings that includeat least one Nitrogen.

The following intermediates are also examples of additional preferredcompounds according to the present invention:

wherein R¹, R² and R⁴ are as defined above;

wherein, in each of the immediately foregoing formulas, each of R¹, R²,R³ and R⁴ are as previously defined herein. These intermediates areuseful in the synthesis of compounds of formula I.

The compounds disclosed herein and covered by the above formulae mayexhibit tautomerism or structural isomerism. It is intended that theinvention encompasses any tautomeric or structural isomeric form ofthese compounds, or mixtures of such forms, and is not limited to anyone tautomeric or structural isomeric form utilized within the formulaedrawn above.

Synthesis of Compounds of Formula I

The compounds of the invention may be prepared by processes known in theart. Suitable processes for synthesizing these compounds are provided inthe examples. Generally, these compounds may be prepared according tothe synthesis schemes provided below.

Compound 1 is either available from commercial sources or is synthesizedby methods known in the art.

wherein R^(1′) can be any of the options for R¹ as defined above and,similarly, R^(3′) can be any of the options for R³ as defined above.

Several substitutions may be obtained by chemical modification ofexisting functional groups using known methods as is exemplified inscheme 4 above. For example, when the desired R¹═NH₂, this substitutionmay be obtained by reduction of the corresponding nitro group.Similarly, when the desired R¹═NHR′ (where R′═—COR¹², —SO₂R¹³, or—R¹⁰R¹¹), this substitution may be obtained by reaction of thecorresponding R¹═NH₂compound with an acid halide or anhydride. When thedesired R¹═CONRR″ (where R=hydrogen or lower alkyl, and R″=lower alkyl),this substitution may be obtained by reaction of the correspondingcompound where R¹═I, with carbon monoxide and a primary or secondaryamine in the presence of a palladium catalyst.

In addition, if R³ in the starting material is CO₂Et, standard chemicalmodification may be used to produce compounds having the followingcorresponding R³groups:

CH₂OH (reduction); CHO (partial reduction); CH₂NMe₂ (reductive aminationof the aldehyde); CH₂OMe (alkylation of the alcohol); CH═CH₂(olefination of the aldehyde); CONRR″ (where R═H or lower alkyl and R″═Hor lower alkyl, aminolysis with the corresponding amine HNRR″ where R═Hor lower alkyl and R″═H or lower alkyl); CONHNHR (where R═H, lower alkylor aryl) (hydrazinolysis—reaction with hydrazine); CN (dehydration ofthe amide CONH₂).

In the foregoing schemes, compound 1 is either commercially available,for example from Sigma, or can be readily synthesized by methods knownin the art. Thus, compound 2 is prepared from the corresponding lactam(compound 1) by the procedure of Sternbach et al., J. Org. Chem. 29:231(1964) or by reaction with Lawesson's reagent.

Compositions/Formulations

In an alternative embodiment, the present invention is directed topharmaceutical compositions comprising at least one compound of formulaI or a prodrug thereof, or a pharmaceutically acceptable salt of acompound of formula I or a prodrug of such compound.

These pharmaceutical compositions can be administered orally, forexample, in the form of tablets, coated tablets, dragees, hard or softgelatin capsules, solutions, emulsions or suspensions. They can also beadministered rectally, for example, in the form of suppositories, orparenterally, for example, in the form of injection solutions.

The pharmaceutical compositions of the present invention comprisingcompounds of formula I, prodrugs of such compounds, or the saltsthereof, may be manufactured in a manner that is known in the art, e.g.by means of conventional mixing, encapsulating, dissolving, granulating,emulsifying, entrapping, dragee-making, or lyophilizing processes. Thesepharmaceutical preparations can be formulated with therapeuticallyinert, inorganic or organic carriers. Lactose, corn starch orderivatives thereof, talc, steric acid or its salts can be used as suchcarriers for tablets, coated tablets, dragees and hard gelatin capsules.Suitable carriers for soft gelatin capsules include vegetable oils,waxes and fats. Depending on the nature of the active substance, nocarriers are generally required in the case of soft gelatin capsules.Suitable carriers for the manufacture of solutions and syrups are water,polyols, saccharose, invert sugar and glucose. Suitable carriers forinjection are water, alcohols, polyols, glycerine, vegetable oils,phospholipids and surfactants. Suitable carriers for suppositories arenatural or hardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifyingagents, sweetening agents, coloring agents, flavoring agents, salts forvarying the osmotic pressure, buffers, coating agents or antioxidants.They can also contain other therapeutically valuable substances,including additional active ingredients other than those of formula I.

Dosages

As mentioned above, the compounds of formula I, prodrugs thereof, andtheir salts, and compositions containing these compounds are useful inthe treatment or control of cell proliferative disorders, in particularoncological disorders. These compounds and formulations containing saidcompounds are particularly useful in the treatment or control of solidtumors, such as, for example, breast and colon tumors.

A therapeutically effective amount of a compound in accordance with thisinvention means an amount of compound that is effective to prevent,alleviate or ameliorate symptoms of disease or prolong the survival ofthe subject being treated. Determination of a therapeutically effectiveamount is within the skill in the art.

The therapeutically effective amount or dosage of a compound of formulaI can vary within wide limits and will be adjusted to the individualrequirements in each particular case. In general, in the case of oral orparenteral administration to adult humans weighing approximately 70 Kg,a daily dosage of about 10 mg to about 10,000 mg, preferably from about200 mg to about 1,000 mg, should be appropriate, although the upperlimit may be exceeded when indicated. The daily dosage can beadministered as a single dose or in divided doses, or for parenteraladministration, it may be given as continuous infusion.

EXAMPLES

The compounds of the present invention may be synthesized according toknown techniques, such as for example the general schemes providedabove. The following examples illustrate preferred methods forsynthesizing the compounds and formulations of the present invention.

In the following examples the NMR data is provided in ppm relative totetramethylsilane, in the solvent and spectrometer frequency asindicated.

Example 1 Pyrazoles Prepared According to Scheme 1

Step a: Reaction of Lactam (Compound 1) with Lawesson's Reagent to FormThiolactam (Compound 2):

1.1 Compound A1: R¹═H, R²═, R⁴═H

To a solution of 5.085 g (20 mmol) of lactam 1 (where R¹═H, R²═F, andR⁴═H) in 50 mL of dimethoxyethane at 75° C. was added 8.9 g (22 mmol) ofLawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide;Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. -O., Bull.Soc. Chim. Belg., 1978, 87:223.). The mixture was stirred for 30minutes, cooled and then poured into 10% sodium bicarbonate solution(aq.). The aqueous mixture was extracted with methylene chloride, andthe extracts washed with water, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue wasrecrystallized from methylene chloride-methanol to give 4.0 g ofCompound A1 (thiolactam 2).

¹H nmr: (DMSO-d6, 300 mHz) 12.56 (s, 1H, NH), 7.10-7.65 (m, 8H), 4.59(s, 2H).

1.2 Compound A2: R¹═F, R²═R⁴═H

Compound A2 was prepared in the same manner as described above forCompound A1. ¹H nmr: (DMSO-d6, 300 mHz) 12.50 (s, 1H, NH), 7.37-7.56 (m,7H), 7.06 (dd, J=3, 9 Hz, 1H), 4.60 (br s, 2H).

Step b: Reaction of Thiolactam 2 With DMF Acetal To FormDimethylaminomethylene Derivative 3:

1.3 Compound A3: R¹═Cl, R²═Cl, R⁴═H

A solution of 0.999 g (3.1 mmol) of thiolactam 2 (R¹═Cl, R²═Cl, R⁴═H),10 mL of dry tetrahydrofuran and 10 mL of dimethylformamide diethylacetal was stirred at room temperature for 2 hours. Volatiles wereremoved under reduced pressure leaving a red-orange solid residue.Crystallization from hexane-ethyl acetate gave 0.716 g of Compound A3(derivative 3 where R¹═Cl, R²═Cl, R⁴═H), as a red solid, mp 196-198° C.¹H nmr: (DMSO-d6, 400 mHz) 10.21 (s, 1H), 7.84 (s, 1H), 7.43-7.56 (m,4H), 7.32 (dd, J=3, 9 Hz, 1H), 7.00 (d, J=9 Hz, 1H), 6.60 (d, J=3Hz,1H), 3.27 (s, 6H).

Step c: Conversion of Dimethylaminomethylene Derivative 3 to Pyrazole 4:

1.4 Compound A4: R¹═Cl, R²═Cl, R³═R⁴═H

5-(2-chlorophenyl)-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

To a solution of 0.265 g (0.71 mmol) in 10 mL of dry methylene chloridewas added ca. 39.8 microliters (1.27 mmole) of anhydrous hydrazine. Themixture was stirred under an argon atmosphere for 85 min., then taken upin methylene chloride and washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give 0.219g of Compound A4 (pyrazole 4 where R¹═Cl, R²═Cl, R⁴═H) as a tan solid.The analytical sample was filtered through a short bed of silica gel,eluting with ethyl acetate, and then recrystallized from ethyl acetate.mp>300° C.

¹H nmr: (DMSO-d6, 400 mHz) 12.07 (s, 1H, NH), 8.03 (s, 1H, NH), 7.58 (s,1H), 7.4-7.5 (m, 4H), 7.17 (dd, J=2, 9 Hz, 1H), 6.79 (d, J=9 Hz, 1H),6.25 (s, 1H).

The following pyrazoles (compound 4) were prepared in accordance withscheme 1 and as described in steps a-c above:

1.5 Compound A5: R¹═NO₂, R²═Cl, R³═H, R⁴═H

5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 9.16 (s, 1H, NH), 7.90 (dd, J=2, 8 Hz, 1H),7.4-7.6 (m, 5 H), 7.08 (d, J=2 Hz, 1 H), 6.75 (d, J=8 Hz, 1H).

1.6 Compound A6: R¹═Cl, R²═H, R³═H, R⁴═H

5-phenyl-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 200 mHz) 7.97 (s, 1H, NH), 7.62 (s, 1H), 7.35-7.60 (m,5H), 7.29 (dd, J=2, 9 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.60 (d, J=2 Hz,1H).

1.7 Compound A7: R¹═Cl, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.10 (s, 1H, NH), 8.01 (s, 1H), 7.60 (s,1H), 7.5 (m, 2H), 7.18-7.33 (m, 3H), 6.83 (d, J=8 Hz, 1H), 6.47 (s, 1H).

1.8 Compound A8: R¹═Cl, R²═Cl, R³═H, R⁴═Cl

5-(2,4-dichlorophenyl)-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6,400 mHz) 12.09 (s, 1H, NH), 8.05 (s, 1H, NH), 7.68 (s,1H), 7.56 (s, 1H), 7.52 (d, J=10 Hz, 1H), 7.48 (d, J=10 Hz, 1H), 7.19(dd, J=2, 9 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 6.27 (d, J=2 Hz, 1H).

1.9 Compound A9: R¹═H, R²═H, R³═H, R⁴═H

5-phenyl-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.04 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H),7.32-7.47 (m, 5H), 7.22 (dt, J=2, 8 Hz,1 H), 6.92 (d, J=8 Hz,1 H), 6.76(d, J=8 Hz, 1H), 6.67 (dd, J=1,8 Hz, 1H).

1.10 Compound A10: R¹═H, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 200 mHz) 12.00 (s, 1H, NH), 7.79 (s, 1H), 7.32-7.56(m, 3H), 7.00-7.32 (m, 3H), 6.78 (d, J=6 Hz,1 H), 6.64 (t, J=6 Hz, 1 H),6.48 (d, J=6 Hz, 1H).

1.11 Compound A11: R¹═F, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-fluoro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 200 mHz) 12.10 (s, 1H, NH), 7.85 (s, 1H), 7.4-7.7 (m,3H), 7.18-7.39 (m, 2H), 7.05 (m, 1H), 6.86 (m, 1H), 6.26 (br d, J=8 Hz,1H).

1.12 Compound A12: R¹═CH₃O, R²═Cl, R³═H, R⁴═H

5-(2-chlorophenyl)-7-methoxy-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 200 mHz) 12.00 (s, 1H, NH), 7.35-7.60 (m, 5H), 6.81(d, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 5.89 (s, 1H), 3.46 (s, 3H).

1.13 Compound A13: R¹═NO₂, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.14 (s, 1H, NH), 9.06 (s, 1H, NH), 7.89(dd, J=2, 9 Hz, 1H), 7.55 (s, 1H), 7.4-7.5 (m, 2H), 6.76 (d, J=9 Hz,IH).

1.14 Compound A14: R¹═CH₃SO₂, R²═H, R³═H, R⁴═H

5-phenyl-7-methanesulfonyl-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.18 (s, 1H, NH), 8.54 (s, 1H, NH), 7.72(dd, J=2, 9 Hz, 1H), 7.64 (s, 1H), 7.43 (m, 5H), 7.14 (d, J=2, Hz, 1H),7.06 (d, J=9 Hz, 1H), 3.01 (s, 3H).

1.15 Compound A15: R¹═CN, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-cyano-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.16 (s, 1H, NH), 8.63 (s, 1H, NH), 7.59 (s,1H), 7.4-7.58 (m, 3H), 7.2-7.37 (m, 2H), 6.82 (dd, J=2,8 Hz, 1H), 6.78(s, 1H).

1.16 Compound A16: R¹═NO₂, R²═H, R³═H, R⁴═H

5-phenyl-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.19 (s, 1H, NH), 8.96 (s, 1H, NH), 8.03(dd, J=2,9 Hz, 1H), 7.62 (s, 1H), 7.35-7.5 (m, 6H), 6.94 (d, J=9 Hz,1H).

1.17 Compound A17: R¹═NO₂, R²═CF₃, R³═H, R⁴═H

5-(2-trifluoromethylphenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.12 (s, 1H, NH), 9.18 (s, 1H, NH), 7.45-7.9(m, 6H), 7.00 (s, 1H), 6.71 (d, J=9 Hz, 1H).

1.18 Compound A18: R¹═CO₂CH₃, R²═H, R³═H, R⁴═H

5-phenyl-7-carbomethoxy-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.15 (s, 1H, NH), 8.42 (s, 1H, NH), 7.78(dd, J=2,9 Hz, 1H), 7.62 (s, 1H), 7.35-7.45 (m, 5 H), 7.29 (d, J=2 Hz,1H), 6.93 (d, J=9 Hz, 1H), 3.66 (s, 3H).

1.19 Compound A19: R¹═I, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-iodo-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.09 (s, 1H, NH), 7.99 (s, 1H, NH), 7.58 (s,1H), 7.4-7.55 (m, 3H), 7.19-7.35 (m, 2H), 6.76 (s, 1H), 6.62 (d, J=8 Hz,1H).

1.20 Compound A20: R¹═CO₂Et, R²═F, R³═H, R⁴═H

5-(2-fluorophenyl)-7-carboethoxy-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.08 (s, 1H, NH), 8.50 (s, 1H, NH), 7.62 (d,J=8 Hz, 1H), 7.57 (s, 1H), 7.4-7.5 (m, 2H), 7.18-7.35 (m, 2H), 7.14 (s1H), 6.80 (d, J=8 Hz, 1H), 4.15 (q, J=6 Hz, 2H), 1.17 (t, J=6 Hz, 3H).

1.21 Compound A21: R¹═H, R²═Cl, R³═H, R⁴═H

5-(2-chlorophenyl)-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.95 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H),7.53 (s, 1H), 7.38-7.48 (m, 4H), 7.09 (t, J=8 Hz, 1H), 6.78 (d, J=8Hz,1H), 6.61 (t, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H).

Example 2 Conversion of Thiolactam 2 to Substituted Pyrazole 7 inAccordance with Schemes 2 and 3

2.1 Compound B1: R¹═NO₂, R²═Cl, R³═2-pyrrolyl, R⁴═H; Scheme 2

3-(2-pyrrolyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

A mixture of 0.995 g (3 mmol) of thiolactam 2 (R¹═NO₂, R²═Cl,R³═2-pyrrolyl, R⁴═H), 0.571 g (6 mmol) of pyrrole-2-carboxaldehyde,0.383 g (4.5 mmol) (Aldrich) of piperidine and 10 mL of dimethoxyethanewas stirred under argon for 2 hours. The mixture was taken up in ethylacetate, and washed successively with 0.1 M sulfuric acid, water andthen brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The corresponding olefin 5 wasisolated by silica gel chromatography (elution with hexane/ethyl acetate(1:1)) as a red solid (0.309 g) and used directly in the next step.Olefin 5 (0.309 g) was dissolved in 6 mL of dimethyl sulfoxide andreacted with 72.5 mg (2.2 mmol) of hydrazine under an argon atmosphere.After 20 min, the mixture was taken up in ethyl acetate and washedsuccessively with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a mixture ofdihydropyrazoles 6 (0.296 g). The mixture of 6 was dissolved in dimethylsulfoxide and heated in the presence of air at 130° C. for 2 hours,cooled, taken up in ethyl acetate, and washed successively with waterand then brine. The extract was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The product, CompoundB1, 7 was purified by silica gel chromatography (elution withhexane-ethyl acetate 25/75).

¹H nmr: (DMSO-d6, 300 mHz) 12.12 (s, 1H, NH), 10.39 (s, 1H, NH), 9.07(s, 1H, NH), 7.96 (dd, J=2, 8 Hz, 1 H), 7.4-7.65 (m, 4H), 7.15 (d, J=2Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8 Hz, 1H), 6.48 (s, 1H), 6.12 (d,J=2Hz, 1H).

2.2 Compound B2: R¹═NO₂, R²═Cl, R³═CO₂Et, R⁴═H; Scheme 3

3-carboethoxy-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

A mixture of 5.0 g (15.1 mmol) of thiolactam 2 (R¹═NO₂, R²═Cl), 6 mL ofa 50% solution of ethyl glyoxylate in toluene, 4.5 mL (31 mmol) ofdiazabicycloundecane and 100 mL of dimethoxyethane was stirred under anargon atmosphere for 30 minutes at room temperature. The mixture wasacidified with 0.005 M H₂SO₄, extracted with ethyl acetate. The combinedextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The aidol adduct 8 was obtained asa mixture of diastereomers (5.6 g) by silica gel chromatography (elutionwith hexane-ethyl acetate 60/40).

A mixture of 4.7 g (10.8 mmol) of aldol adduct 8 obtained above, 100 mLof pyridine and 6.9 mL (54.4 mmol) of chlorotrimethylsilane was stirredfor 10 minutes at room temperature and then heated at 120° C. for 1.5hours. The mixture was cooled, taken up in 1 L of ethyl acetate andwashed successively with water and brine, and the ethyl acetate layerdried over anhydrous sodium sulfate. After filtration and evaporation ofvolatiles under reduced pressure, the crude residue was filtered throughsilica gel, eluting with hexane-ethyl acetate (1:1), to give 4.3 g ofolefin 5.

A solution of 4.3 g of olefin 5, obtained above, in 210 mL ofdichloromethane, was stirred with 0.68 mL (21.6 mmol) of anhydroushydrazine for 30 min. The mixture was then partitioned between water,and the aqueous phase extracted with dichloromethane. The combinedextracts were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue, which contained amixture of dihydropyrazoles 6, was dissolved in 50 mL ofdimethylsulfoxide and heated at 130° C. in the presence of air for 3hours. The reaction mixture was cooled, taken up in ethyl acetate andwashed with water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The productwas isolated by silica gel chromatography, eluting with hexane-ethylacetate (40/60) to give 0.580 g of Compound B2 (R¹═NO₂, R²═Cl, R³═CO₂Et,R⁴═H).

¹H nmr: (DMSO-d6, 400 mHz) 13.33 (s, 1H), 9.15 (s, 1H), 8.02 (dd, J=2, 9Hz, 1H), 7.46-7.55 (m, 4H), 7.18 (d, J=2 Hz, 1H), 6.89 (d, J=9 Hz, 1H),4.25 (q, J=7 Hz, 2H), 1,27 (t, J=7 Hz, 3H).

The following pyrazoles (compound 7) were prepared in accordance withscheme 2 or 3 as described above:

2.3 Compound B3: R¹═NO₂, R²═Cl, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.85 (s, 1H, NH), 9.04 (s, 1H, NH), 7.83(dd, J=2, 9 Hz, 1 H), 7.39-7.52 (m, 4H), 7.05 (d, J=2 Hz, 1H), 6.69 (d,J=9 Hz,1H), 1.98 (s, 3H).

2.4 Compound B4: R¹═NO₂, R²═Cl, R³═CH₂CH₃, R⁴═H (Scheme 2)

3-ethyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.91 (s, 1H, NH), 9.05 (s, 1H, NH), 7.85(dd, J=2, 8 Hz,1H), 7.35-7.58 (m, 4H), 7.04 (d, J=2 Hz,1H), 6.71 (d, J=8Hz, 1H), 2.41 (q, J=7 Hz, 2H), 1.06 (t, J=7 Hz, 3H).

2.5 Compound B5: R¹═NO₂, R²═Cl, R³═CH₂CH₂Ph, R⁴═H (Scheme 2)

3-(2-phenylethyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 200 mHz) 11.95 (s, 1H, NH), 9.05 (s, 1H, NH), 7.82(dd, J=2, 8 Hz, 1H), 7.05-7.60 (m, 10H), 6.70 (d, J=8 Hz, 1H), 2.82 (m,2H), 2.64 (m, 2H).

2.6 Compound B6: R¹═NO₂, R²═Cl, R³═i-Pr, R⁴═H (Scheme 2)

3-(1-methylethyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.90 (s, 1H, NH), 9.02 (s, 1H, NH), 7.84(dd, J=2, 9 Hz, 1H), 7.35-7.55 (m, 4H), 7.04 (d, J=2 Hz, 1H), 6.74 (d,J=9 Hz, 1H), 2.86 (sept, J=9 Hz, 1H), 1.14 (d, J=9 Hz, 6H).

2.7 Compound B7: R¹═CN, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine-7-carbonitrile

¹H nmr: (DMSO-d6, 300 mHz) 12.05 (s, 1H, NH), 8.55 (s, 1H, NH), 7.45 (m,3H), 7.25 (m, 2H), 6.78 (d, J=8 Hz, 1H), 6.71 (s, 1H), 2.03 (s, 3H).

2.8 Compound B8: R¹═NO₂, R²═Cl, R³═CH₂Ph, R⁴═H (Scheme 2)

3-(phenylmethyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.08 (s, 1H, NH), 9.08 (s, 1H), 7.85 (d, J=9Hz, 1H), 7.40-7.56 (m, 4H), 7.16-7.34 (m, 5H), 7.06 (brs, 1H), 6.71 (d,J=9 Hz, 1H), 3.71 (s, 2H).

2.9 Compound B9: R¹═CO₂Et, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-7-carboethoxy-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J=2, 9Hz, 1H), 7.39-7.51 (m, 2H), 7.16-7.31 (m, 2H), 7.09 (s, 1H), 6.74 (d,J=9 HZ, 1H), 4.08 (q, J=7 Hz, 2H), 2.04 (s, 3H), 1.12 (t, J=7 Hz, 3H).

2.10 Compound B10: R¹═NO₂, R²═Cl, R³=5-(4-Me)-pyrazolyl, R⁴═H (Scheme 2)

3-(4-methylpyrazol-5-yl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.58 (s, 1H), 9.26 (s, 1H), 8.75 (brs, 1H),7.95 (d, J=8 Hz, 1H), 7.42-7.6 (m, 5H), 7.12 (s, 1H), 6.81 (d, J=8 Hz,1H) 2.32 (s, 3H).

2.11 Compound B11: R¹═NO₂, R²═Cl, R³═CH₂-iPr, R⁴═H (Scheme 2)

3-(2-methylpropyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 11.91 (s,1 H), 9.06 (s, 1H), 7.87 (dd, J=2, 9Hz, 1H), 7.4-7.56 (m, 4H), 7.08 (d, J=2 Hz, 1H), 6.74 (d, J=9 Hz, 1H),

2.28 (d, J=7 Hz, 2H), 1.89 (n, J=7 Hz, 1H), 0.88 (d, J=7 Hz, 6H).

2.12 Compound B12: R¹═NO₂, R²═Cl, R³═CF₃, R⁴═H (Scheme 3)

3-trifluoromethyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (CDCl₃+DMSO-d6, 300 mHz) 7.98 (dd, J=2, 9 Hz, 1H), 7.2-7.6 (m,6H), 7.02 (br s, 1H), 6.62 (d, J=9 Hz, 1H).

2.13 Compound B13: R¹═NO₂, R²═Cl, R³=1-thiazolyl, R⁴═H (Scheme 3)

3-(1-thiazolyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 13.08 (s, 1H), 9.21 (s, 1H), 7.88-7.92 (m,2H), 7.84 (d, J=3 Hz, 1H), 7.42-7.62 (m, 4H), 7.12 (d, J=2 Hz, 1H), 6.79(d, J=8 Hz, 1H).

2.14 Compound B14: R¹═NO₂, R²═Cl, R³=4-imidazolyl, R⁴═H (Scheme 2)

3-(4-imidazolyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.33 (s, 1H), 12.29 (s, 1H), 9.07 (s, 1H),7.90 (dd, J=2, 9 Hz,1H), 7.76 (s, 1H), 7.44-7.63 (m, 4H), 7.35 (s, 1H),7.11 (d, J=2 Hz, 1H), 6.78 (d, J=9 Hz, 1H).

2.15 Compound B15: R¹═NO₂, R²═Cl, R³=2-pyrazolyl, R⁴═H (Scheme 2)

3-(2-pyrazolyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 13.11 (s, 1H), 12.48 (s, 1H), 9.12 (s, 1H),7.93 (d, J=9 Hz, 1H), 7.76 (s, 1H), 7.39-7.60 (m, 4H), 7.11 (s, 1H),6.78 (=9 Hz, 1H), 6.59 (s, 1H).

2.16 Compound B16: R¹═NO₂, R²═Cl, R³=3-pyrazolyl, R⁴═H (Scheme 2)

3-(3-pyrazolyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 13.09 (s, 1H), 12.31 (s, 1H), 9.13 (s, 1H),7.80-8.05 (m, 4H), 7.40-7.62 (m, 3H), 7.13 (s, 1H), 6.78 (d, J=9 Hz,1H).

2.17 Compound B17: R¹═NO₂, R²═Cl, R³═CH(Me)CH₂Me, R⁴═H (Scheme 2)

3-(1-methylpropyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.90 (s, 1H), 9.04 (s, 1H), 7.85 (dd, J=2, 9Hz, 1H), 7.38-7.55 (m, 4H), 7.05 (d, J=2 Hz, 1 H), 6.72 (d, J=9 Hz, 1H),2.65 (m, 1H), 1.52 (m, 2H), 1.13 (d, J=7 Hz, 3H), 0.79 (t, J=8 Hz, 3H).

2.18 Compound B18: R¹═MeO, R²═Cl, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-chlorophenyl)-7-methoxy-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.69 (s, 1H), 7.34-7.50 (m, 5H), 6.77 (dd,J=2, 9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.86 (d, J=9 Hz, 1H), 5.86 (d, J=2Hz, 1H), 3.44 (s, 3H), 2.05 (s, 3H).

2.19 Compound B19: R¹═Cl, R²═H, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 11.85 (s, 1H), 7.90 (s, 1H), 7.46-7.52 (m,2H), 7.39-7.44 (m, 3H), 7.29 (dd, J=2, 9 Hz, 1H), 6.92 (d, J=9 Hz, 1H),6.62 (d, J=2 Hz, 1H), 2.16 (s, 3H).

2.20 Compound B20: R¹═Cl, R²═Cl, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-chlorophenyl)-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹nmr: (DMSO-d6, 300 mHz) 11.78 (s, 1H), 7.95 (s, 1H), 7.38-7.55 (m, 4H),7.17 (dd, J=2, 9 Hz,1H), 6.75 (d, J=9 Hz, 1H), 6.22 (d, J=2 Hz, 1H),2.03 (s, 3H).

2.21 Compound B21: R¹═H, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.75 (s, 1H), 7.69 (s, 1H), 7.36-7.52 (m,2H), 7.04-7.30 (m, 3H), 6.77 (d, J=8 Hz, 1H), 6.63 (t, J=8 Hz, 1H), 6.50(d, J=8 Hz, 1H), 2.07 (s, 3H).

2.22 Compound B22: R¹═F, R²═H, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-7-fluoro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.85 (s, 1H), 7.70 (s, 1H), 7.46-7.55 (m,2H), 7.35-7.43 (m, 2H), 7.11 (dt, J=3, 9 Hz, 1H), 6.92 (dd, J=5, 9 Hz,1H), 6.41 (dd, J=3, 10 Hz, 1H), 2.14 (s, 3H).

2.23 Compound B23: R¹═NO₂, R²═Cl, R³=phenyl, R⁴═H (Scheme 2)

3-phenyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 12.65 (s, 1H), 9.18 (s, 1H), 7.95 (dd, J=2, 9Hz, 1H), 7.78 (d, J=8 Hz, 2H), 7.32-7.63 (m, 7H), 7.14 (d, J=2 Hz, 1H),6.85 (d, J=9 Hz, 1H).

2.24 Compound B24: R¹═NO₂, R²═Cl, R³=n-propyl, R⁴═H (Scheme 2)

3-propyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 11.91 (s, 1H), 9.06 (s, 1H), 7.86 (d, J=8 Hz,1H), 7.41-7.53 (m, 4H), 7.08 (s, 1H), 6.72 (d, J=8 Hz, 1H), 2.38 (t, J=8Hz, 2H), 1.54 (tq, J=8, 7 Hz, 2H), 0.88 (t, J=7 Hz, 3H).

Compound B25: R¹═NO₂, R²═Cl, R³=cyclopropyl, R⁴═H (Scheme 2)

3-cyclopropyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 400 mHz) 11.72 (s, 1H), 9.05 (s, 1H), 7.87 (dd, J=2, 9Hz, 1H), 7.41-7.55 (m, 4H), 7.08 (d, J=2Hz, 1H), 6.72 (d, J=9 Hz, 1H),1.79 (p, J=7 Hz, 1H), 0.88 (d, J=7 Hz, 4H).

2.26 Compound B26: R¹═F, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-7-fluoro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.82 (s, 1H), 7.76 (s, 1H), 7.41-7.58 (m,2H), 7.18-7.35 (m, 2H), 7.05 (dt, J=3, 9 Hz, 1H), 6.84 (dd, J=6, 9 Hz,1H), 6.25 (dd, J=3, 9 Hz, 1H), 2.08 (s, 3H).

2.27 Compound B27: R¹═NO₂, R²═H, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

2.28 Compound B28: R¹═H, R²═H, R¹═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.78 (s, 1H), 7.66 (s, 1H), 7.47 (m, 2H),7.39 (m, 3H), 7.20 (dt, J=1, 8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 6.75 (t,J=8 Hz, 1H), 6.68 (dt, J=1, 8 Hz, 1H), 2.14 (s, 3H).

2.29 Compound B29: R¹═I, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-7-iodo-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 7.90 (s, 1H), 7.39-7.57 (m,3H), 7.18-7.36 (m, 2H), 6.75 (s, 1H), 6.59 (d, J=9 Hz, 1H), 2.07 (s, 3H)

2.30 Compound B30: R¹═H, R²═Cl, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-chlorophenyl)-pyrazolo[3,4][1,4]benzodiazepine

2.31 Compound B31: R¹═NO₂, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.90 (s, IH), 9.00 (s, IH), 7.87 (dd, J=3, 9Hz, 1H), 7.47 (m, 2H), 7.18-7.32 (m, 3H), 6.73 (d, J=9 Hz, 1H), 2.02 (s,3H).

2.32 Compound B32: R¹═Cl, R²═F, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-(2-fluorophenyl)-7-chloro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.81 (s, 1H), 7.96 (s, 1H), 7.40-7.55 (m,2H), 7.17-7.32 (m, 3H), 6.79 (d, J=9 Hz, 1H), 6.42 (s, 1H), 2.08 (s,3H).

2.33 Compound B33: R¹═I, R²═H, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-7-iodo-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.82 (s, 1H), 7.85 (s, 1H), 7.36-7.55 (m,6H), 6.91 (d, J=2 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 2.15 (s, 3H).

2.34 Compound B34: R¹═Br, R²═H, R³═CH₃, R⁴═H (Scheme 2)

3-methyl-5-phenyl-7-bromo-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 7.89 (s, 1H), 7.49 (m, 2H), 7.38 (m, 4H),6.85 (d, J=9 Hz, 1H), 6.74 (d, J=2 Hz, 1H), 2.15 (s, 3H).

2.35 Compound B35: R¹═CN, R²═F, R³═—CH₂OH, R⁴═H (Shceme 3)

3-hydroxymethyl-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]-benzodiazepine-7-carbonitrile.

Example 3 Functional Group Modification in Accordance with Scheme 4

As mentioned above with reference to Scheme 4, certain compounds may beeasily obtained by transformation of existing functional groups. Severalof these transformations are further exemplified below.

A. Substitution of Iodo by Carbonyl: R¹═I to R¹═CONRR′

3.1 Compound C1: R¹═CON(—CH₂CH₂—O—CH₂CH₂—), R²═F, R³═H, R

5-(2-fluorophenyl)-7-morpholinylcarbonyl-pyrazolo[3,4][1,4]benzodiazepine

A mixture of 0.0712 g (0.17 mmol) of pyrazole 4 (R¹═I, R²═F, R³═H,R⁴═H), 0.0082 g (0.0012 mmol) of bis triphenylphosphine palladiumdichloride catalyst, 1 mL of morpholine was stirred and heated (75° C.)under an atmosphere of carbon monoxide for 90 minutes. The mixture wascooled, and then purified by chromatography on reverse phase silica gel(gradient elution with water-acetonitrile) to give 0.06 g of Compound C1(pyrazole 4 wherein R¹═CON(—CH₂CH₂—O—CH₂CH₂—), R²═F, R³═H, R⁴═H).

¹H nmr: (DMSO-d6, 300 mHz) 12.05 (s, 1H, NH), 8.18 (s, 1H, NH), 7.59 (s,1H), 7.4-7.5 (m, 2H), 7.18-7.35 (m, 3H), 6.84 (d, J=9 Hz, 1H), 3.25 (m,8H).

The following compounds were prepared using method A above:

3.2 Compound C2: R¹═CONHCH₂CH₂OH, R²═F, R³═H, R⁴═H

N-(2-hydroxyethyl)-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide

¹H nmr: (DMSO-d6, 300 mHz) 12.08 (s, 1H, NH), 8.20 (s, 1H, NH), 8.16 (m,1H, NH), 7.61 (d, J=9 Hz, 1H), 7.57 (s, 1H), 7.4-7.5 (m, 2H), 7.14-7.3(m, 2H), 7.11 (s, 1H), 6.89 (d, J=9 Hz, 1H), 4.63 (m, 1H, OH), 3.40 (m,2H), 3.18 (m, 2H).

3.3 Compound C3: R¹═CON(CH₂CH₂OH)₂, R²═F, R³═H, R⁴═H

N, N-bis-(2-hydroxyethyl)-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide

¹H nmr: (DMSO-d6, 300 mHz) 12.10 (s, 1H, NH), 8.11 (s, 1H, NH), 7.59 (s,1H), 7.4-7.52 (m, 2H), 7.15-7.3 (m, 3H), 6.80 (d, J=9 Hz, 1H), 6.58 (s,1H), 4.65 (m, 2H, OH), 3.30 (m, 8H).

B. Reduction of the Nitro to Amino: R¹═NO₂ to R¹═NH₂ 3.4 Compound C4:R¹═NH₂, R²═Cl, R³═CH₃, R⁴═H

3-methyl-5-(2-chlorophenyl)-7-amino-pyrazolo[3,4][1,4]benzodiazepine

A solution of 0.20 g (0.57 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CH₃,R⁴═H) in 8 mL of ethanol was stirred at room temperature under ahydrogen atmosphere with Raney nickel (0.5 mL of a 50% slurry in water,washed with ethanol just prior to use). After 4 hours, the mixture wasfiltered, and concentrated under reduced pressure to give 0.177 g ofCompound C4 (amino derivative 7 wherein R¹═NO₂, R²═Cl, R³═CH₃, R⁴═H).mp. 260-263° C.

¹H nmr: (DMSO-d6, 300 mHz) 11.62 (s, 1H), 7.38-7.47 (m, 4H), 7.07 (s, s,1H), 6.53 (d, J=8 Hz, 1H), 6.38 (dd, J=2, 9 Hz,1H), 5.74 (d, J=2 Hz,1H), 4.52 (s, 2H), 2.06 (s, 3H).

The following compounds were prepared using method B above:

3.5 Compound C5: R¹═NH₂, R²═Cl, R³═H, R⁴═H

5-(2-chlorophenyl)-7-amino-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (CD₃OD, 300 mHz) 7.35-7.55 (m, 5 H), 6.72 (dd, J=3, 7 Hz, 1H),6.62 (d, J=7 Hz, 1H), 6.13 (d, J=3 Hz, 1H).

3.6 Compound C6: R¹═NH₂, R²═Cl, R³=I-Pr, R⁴═H

3-(1-methylethyl)-5-(2-chlorophenyl)-7-amino-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 11.65 (2, 1 H), 7.38-7.4 (m, 4H), 7.08 (s,1H), 6.75 (d, J=8 Hz, 1H), 6.39 (dd, J=2, 8 Hz, 1H), 5.74 (d, J=2 Hz,1H), 2.98 (sept, J=7 Hz, 1H), 1.18 (d, J=7 Hz, 6H).

C. Derivitization of Amino Compounds: R¹═NH₂ to R¹═NHR′ (as Defined inScheme 4 supra)

3.7 Compound C7: R¹═NHAc, R²═Cl, R³ =CH₃, R⁴═H

N-(3-methyl-5-(2-chlorophenyl)-pyrazolo[3,4][1,4]benzodiazepin-7-yl)-acetamide

A suspension of 0.323 g (1 mmol) of pyrazole 7 (R¹═NH₂, R²═Cl, R³═CH₃,R⁴═H) in 20 mL of dichloromethane was reacted with 0.112 g (1.1 mmol) ofacetic anhydride under an inert atmosphere at room temperature for 2hours. The mixture was then diluted with ethyl acetate and washedsuccessively with water and brine. The aqueous layers were extractedwith ethyl acetate, and the combined extracts dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theproduct was isolated by silica gel chromatography eluting withhexane-ethyl acetate (30/70) to give 0.175 g of Compound C7.

¹H nmr: (DMSO-d6, 300 mHz) 11.71 (s, 1H), 9.56 (s, 1H), 7.56 (s, 1H),7.38-7.57 (m, 5H), 6.67 (d, J=8 Hz, 1H), 6.57 (d, J=2 Hz, 1H), 2.05 (s,3H), 1.83 (s, 3H).

The following compounds were prepared analogously to Compound C7 inaccordance with Method C above:

3.8 Compound C8: R¹=AcryloylNH, R²═Cl, R³═CH₃, R⁴═H

N-(3-methyl-5-(2-chlorophenyl)-pyrazolo[3,4][1,4]benzodiazepin-7-yl)-2-propenamide

¹H nmr: (DMSO-d6, 300 mHz) 11.71 (s, 1H), 9.78 (s, 1H), 7.63 (s, 1H),7.52 (dd, J=2, 9 Hz, 1H), 7.35-7.50 (m, 4H), 6.71 (d, J=9 Hz, 1H), 6.69(d, J=2 Hz, 1H), 6.23 (dd, J=10, 18 Hz, 1H), 6.08 (dd, J=2, 18 Hz,1H),5.60 (dd, J=2, 10 Hz, 1H), 2.05 (s, 3H).

3.9 Compound C9: R¹═CH₃SO₂NH, R²═Cl, R³═CH₃, R⁴═H

N-(3-methyl-5-(2-chlorophenyl)-pyrazolo[3,4][1,4]benzodiazepin-7-yl)-methanesulfonamide

A mixture of 0.323 g (1 mmol) of pyrazole 7 (R¹═NH₂, R²═Cl, R³═CH₃,R⁴═H), 0.122 g (1 mmol) of 4-dimethylaminopyridine and 5 mL oftetrahydrofuran was stirred under an inert atmosphere at roomtemperature for 2 hours. The mixture was diluted with ethyl acetate andwashed successively with water and brine, with reextraction of theaqueous phases with ethyl acetate. The combined ethyl acetate extractswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The product was isolated by silica gelchromatography eluting with hexane-ethyl acetate (10/90) to give 0.244 gof Compound C9 (pyrazole 7 where R¹═CH₃SO₂NH, R²═Cl, R³═CH₃, R⁴═H)(recrystallization from ethyl acetate) mp 196-198° C.

¹H nmr: (DMSO-d6, 300 mHz) 11.74 (s, 1H), 9.12 (s, 1H), 7.71 (s, 1H),7.36-7.46 (m, 4H), 6.94 (dd, J=2, 8 Hz, 1H), 6.72 (d, J=8 Hz, 1H), 6.31(d, J=2 Hz, 1H), 2.70 (s, 3H), 2.05 (s, 3H).

D. Aminolysis of R³═CO₂Et to R³═CONRR′

3.10 Compound C10: R¹═NO₂, R²═Cl, R³═CONH₂, R⁴═H

5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine-3-carboxamide

0.15 g (0.36 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CO₂Et, R⁴═H) wasstirred with a solution of ammonia (15 mL) in ethanol (50 mL) at roomtemperature for 48 hours. Volatiles were removed under reduced pressureand the product purified by silica gel chromatography. Elution withethyl acetate-isopropanol (95/5) gave 0.074 g of Compound C10 (pyrazole7′ wherein R¹═NO₂, R²═Cl, R³═CONH₂, R⁴═H), as a solid. mp>340° C.(recrystallization from ethyl acetate).

¹H nmr: (DMSO-d6, 400 mHz) 12.95 (br s, 1H), 9.23 (br s, 1H), 7.92 (d,J=8 Hz, 1H), 7.81 (s, 1H), 7.45-7.61 (m, 4H), 7.21 (s, 1H), 7.08 (s,1H),6.75 (d, J=8 Hz, 1H).

The following compounds were prepared analogously to Compound C10 usingMethod D above:

3.11 Compound C11: R¹═NO₂, R²═Cl, R³═CONMe₂, R⁴═H

N,N-dimethyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine-3-carboxamide

¹H nmr: (DMSO-d6, 300 mHz) 12.65 (s, 1H), 9.18 (s, 1H), 7.91 (d, J=9 Hz,1H), 7.41-7.55 (m, 4H), 7.08 (s, 1H), 6.75 (d, J=9 Hz, 1H), 3.01 (s,3H), 2.88 (s, 3H).

3.12 Compound C12: R¹═NO₂, R²═Cl, R³═CONHNH₂, R⁴═H

N-amino-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine-3-carboxamide

¹H nmr: (DMSO-d6, 300 mHz) 13.02 (s, 1H), 9.19 (s, 1H), 8.58 (t, J=5 Hz,1H), 7.91 (dd, J=2, 9 Hz, 1H), 7.41-7.62 (m, 4H), 7.09 (d, J=2 Hz, 1H),6.75 (d, J=9 Hz, 1H), 4.54 (d, J=5 Hz, 2H).

E. Reduction of R³═CO₂Et to R³═CHO and R³═CH₂OH

3.13 Compound C13: R¹═NO₂, R²═Cl, R³═CHO, R⁴═H; and Compound C14 R¹═NO₂,R²═Cl, R³═CH₂OH, R⁴═H

A mixture of 0.48 g (1.17 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CO₂Et,R⁴═H) and 30 mL of tetrahydrofuran at −15° C. under an inert atmospherewas treated with 1.52 mL of a 1 M solution of lithium aluminum hydridein tetrahydrofuran for 30 minutes. The mixture was then diluted withethyl acetate and washed successively with aqueous sodium potassiumsulfate and brine, reextracting the organic washes with ethyl acetate.The combined ethyl acetate extracts were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Purificationby silica gel chromatography, eluting with hexane-ethyl acetate gave0.21 g of Compound C13 (pyrazole 7′ wherein R¹═NO₂, R²═Cl, R³═CHO, R⁴═H)as a red solid, and 0.11 g of Compound C14 (pyrazole 7′ wherein R¹═NO₂,R²═Cl, R³═CH₂OH, R⁴═H), also as a red solid.

Compound C13:

5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine-3-carboxaldehyde

¹H nmr: (DMSO-d6, 300 mHz) 13.29 (s, 1H), 9.66 (s, 1H), 9.27 (s, 1H),7.96 (dd, J=2, 9 Hz, 1H), 7.45-7.59 (m, 4H), 7.13 (d, J=2 Hz, 1H), 6.79(d, J=9 Hz, 1H).

Compound C14:

3-hydroxymethyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

¹H nmr: (DMSO-d6, 300 mHz) 12.11 (s, 1H), 9.08 (s, 1H), 7.85 (dd, J=2, 9Hz, 1H), 7.42-7.50 (m, 4H), 7.06 (d, J=2 Hz, 1H), 6.71 (d, J=9 Hz, 1H),5.23 (t, J=5 Hz, 1H), 4.27 (d, J=5 Hz, 2H).

F. Reductive Amination of an Aldehyde: R³═CHO to R³═CH₂NR²

3.14 Compound C15: R¹═NO₂, R²═Cl, R³═CH₂NMe₂, R⁴═H

-(N,N-dimethylaminomethyl)-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

A suspension of 0.142 g (0.39 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl,R³═CHO, R⁴═H), 0.0631 g (0.78 mmol) of dimethylamine hydrochloride, 0.11mL (0.78 mmol) of triethylamine, 0.165 g (1 mmol) of sodiumtriacetoxyborohydride, 0.2 of 4A molecular sieves and 20 mL ofdichloromethane was stirred under an inert atmosphere for 3 hours. Themixture was filtered, diluted with ethyl acetate and washed successivelywith water and brine, reextracting the aqueous phases with ethylacetate. The combined ethyl acetate extracts were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure.Purification by reverse phase silica gel chromatography (gradientelution with water-acetonitrile-trifluoroacetic acid) gave 0.147 g ofCompound C15 (pyrazole 7′ wherein R¹′NO₂, R²═Cl, R³═CH₂NMe₂, R⁴═H) asthe trifluoroacetate salt.

¹H nmr: (DMSO-d6, 300 mHz) 12.54 (s, 1H), 9.92 (s, 1H), 9.25 (s, 1H),7.91 (dd, J=2, 8 Hz, 1H), 7.45-7.55 (m, 4H), 7.10 (d, J=2 Hz, 1H), 6.76(d, J=8 Hz, 1H), 4.08 (s, 2H), 2.75 (s, 6H).

G. Alkylation of Alcohols: R³═CH₂OH to R³═CH₂OCH₃

3.15 Compound C16: R¹═NO₂, R²═Cl, R³═CH₂OCH₃, R⁴═H

3-methoxymethyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

A mixture of 0.075 g (0.2 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CH₂OH,R⁴═H), 0.2 g of silica gel and 20 mL of tetrahydrofuran was stirred witha solution of diazomethane in ether (50 mL, ca. 9.2 mmol). After 2 hoursthe mixture was filtered, concentrated under reduced pressure. Theproduct was purified by chromatography on silica gel, eluting withhexane-ethyl acetate, to give Compound C16 (pyrazole 7′ wherein R¹═NO₂,R²═Cl, R³═CH₂OCH₃, R ⁴═H) as a red solid.

¹H nmr: (DMSO-d6, 300 mHz) 12.27 (s, 1H), 9.11 (s, 1H), 7.86 (dd, J=2, 9Hz, 1H), 7.43-7.50 (m, 4H), 7.06 (d, J=2 Hz, 1H), 6.72 (d, J=9 Hz, 1H),4.20 (s, 2H), 3.25 (s, 3H).

H. Methylenation of Aldehyde: R³═CHO to R³═CHCH₂

3.16 Compound C17: R¹═NO₂, R²═Cl, R³═CHCH₂, R⁴═H

3-ethenyl-5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine

To a solution of methylene triphenylphosphorane, prepared by reaction of0.109 g (0.31 mmol) of methyltriphenylphosphonium bromide in 5 mL oftetrahydrofuran and 0.29 mL of 1 M solution of potassium tert.-butoxidein tetrahydrofuran, at −78° C. under an inert atmosphere, was added0.080 g (0.22 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CHO, R⁴═H). Themixture was warmed to reflux, and stirred overnight, after which themixture was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine. The ethyl acetate extract wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. Purification by silica gel chromatography, elutingwith hexane-ethyl acetate (70/30) gave 0.043 g of Compound C17 (pyrazole7′ wherein R¹═NO₂, R²═Cl, R³═CHCH₂, R⁴═H) as a red solid.

¹H nmr: (DMSO-d6, 300 mHz) 12.33 (s, 1H), 9.11 (s, 1H), 7.88 (dd, J=2,9Hz, 1H), 7.40-7.50 (m, 4H), 7.08 (d, J=2 Hz, 1H), 6.74 (d, J=9 Hz, 1H),6.40 (dd, J=12, 18 Hz, 1H), 5.85 (d, J=18 Hz, 1H), 5.36 (d, J=12 Hz,1H).

I. Dehydration of Amide: R³═CONH₂ to R³═CN

3.17 Compound C18: R¹═NO₂, R²═Cl, R³═CN, R⁴═H

5-(2-chlorophenyl)-7-nitro-pyrazolo[3,4][1,4]benzodiazepine-3-carbonitrile

A mixture of 0.47 g (1.23 mmol) of pyrazole 7 (R¹═NO₂, R²═Cl, R³═CONH₂,R⁴═H), 0.34 g (2.46 mmol) of potassium carbonate, 0.94 g (6.15 mmol) ofphosphorous oxychloride and 20 mL of acetonitrile was heated to refluxfor 4 hours under an inert atmosphere. The mixture was cooled to roomtemperature, diluted with ethyl acetate and washed successively withsaturated aqueous sodium bicarbonate solution, water and brine,reextracting the aqueous phases with ethyl acetate. The combined ethylacetate extracts were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed onsilica gel eluting with hexane-ethyl acetate (70/30) to give 0.24 g ofCompound C18 (pyrazole 7′ wherein R¹═NO₂, R²═Cl, R³═CN, R⁴═H) as anorange solid (recrystallization from dichloromethane). mp 193-196° C. IR(KBr) 2240 cm⁻¹. ¹H nmr: (DMSO-d6, 300 mHz) 9.36 (s, 1H), 7.96 (dd, J=2,9 Hz, 1H), 7.48-7.58 (m, 4H), 7.11 (d, J=2 Hz, 1H), 6.77 (d, J=9 Hz,1H).

J. Nitrile Hydrolysis R¹═CN to R³═CONH₂.

3.18 Compound C19: R¹═CONH₂, R²═F, R³═CH₃, R⁴═H

3-methyl-5-(2-fluorophenyl)-pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide

To a solution of 0.5 g (1.6 mmol) pyrazole 7 (R¹═CN, R²═F, R³═CH₃, R⁴═H)in 79 mL of dimethylsulfoxide was added 47 mL of ice cold hydrogenperoxide (30% aqueous solution) and 24 mL of 1 M sodium hydroxide. Afterthe reaction was complete, the mixture was extracted with ethyl acetate,and the extracts washed successively with water, brine and then driedover anhydrous sodium sulfate. The mixture was filtered, andconcentrated under reduced pressure. Purification by silica gelchromatography (elution with ethyl acetate/methanol (95:5)) gave 0.5 gof Compound C19 (pyrazole 7 wherein R¹═CONH₂, R²═F, R³═CH₃, R⁴═H) as ayellow solid. mp 323-324° C.

¹H nmr: (DMSO-d6, 300 mHz) 11.79 (s, 1H), 8.08 (s, 1H), 7.64 (s, 1H),7.58 (dd, J=2, 9 Hz, 1H), 7.38-7.52 (m, 2H), 7.02-7.30 (m, 4H), 6.73 (d,J=9 Hz, 1H), 2.05 (s, 3H).

Additional compounds not specifically listed in Examples 1-3 above wereprepared using the methods described above. These compounds, designated“D,” are included in Tables I-IV below.

Example 4 Antiproliferative Activity

The antiproliferative activity of the compounds of the invention isdemonstrated below. These effects indicate that the compounds of thepresent invention are useful in treating cancer, in particular solidtumors such as breast and colon tumors.

CDK2 FlashPlate Assay

To determine inhibition of CDK2 activity, purified recombinantretinoblastoma (Rb) protein was coated on 96 well FlashPlates (NewEngland Nuclear, Boston, Mass.). Rb is a natural substrate forphosphorylation by CDK2 (Herwig and Strauss Eurr. J. Biochem., Vol. 246(1997) pp. 581-601 and references therein). Recombinant active humanCyclin E/CDK2 complexes were partially purified from extracts of insectcells. The active Cyclin E/CDK2 was added to the Rb-coated Flash Platesalong with ³³P-ATP and dilutions of test compounds. Plates wereincubated for 25 minutes at room temperature with shaking, then washedand counted in the Topcount scintillation counter (Packard InstrumentCo., Downers Grove, Ill.). Dilutions of test compounds were tested induplicate in each assay. The percent inhibition of Rb phosphorylation,which is a measure of the inhibition of CDK2 activity, was determinedaccording to the following formula:$100 \times \lbrack {1 - \frac{{t\quad e\quad s\quad t\quad c\quad o\quad m\quad p\quad o\quad u\quad n\quad d} - {n\quad o\quad n\quad s\quad p\quad e\quad c\quad i\quad f\quad i\quad c}}{{t\quad o\quad t\quad a\quad l} - {n\quad o\quad n\quad s\quad p\quad e\quad c\quad i\quad f\quad i\quad c}}} \rbrack$where “test compound” refers to the average counts per minute of thetest duplicates, “nonspecific” refers to the average counts per minutewhen no Cyclin E/CDK2 was added, and “total” refers to the averagecounts per minute when no compound was added.

The results of the foregoing in vitro experiments are set forth inTables IA-1C below.

TABLE IA Inhibition of Cdk2 - IC₅₀ Range 0.01-0.99 μM Compound R¹ R² R⁴Number (position 7) (position 2′)* R³ (position 4′) A5 NO₂ Cl H H A13NO₂ F H H A15 CN F H H A16 NO₂ H H H A17 NO₂ CF₃ H H A20 CO₂Et F H H A21H Cl H H B1 NO₂ Cl 2-pyrrolyl H B3 NO₂ Cl CH₃ H B4 NO₂ Cl CH₂CH₃ H B6NO₂ Cl i-Pr H B7 CN F CH₃ H B9 CO₂Et F CH₃ H B10 NO₂ Cl5-(4-Me)-pyrazolyl H B12 NO₂ Cl CF₃ H B13 NO₂ Cl 1-thiazolyl H B14 NO₂Cl 4-imidazolyl H B15 NO₂ Cl 2-pyrazolyl H B16 NO₂ Cl 3-pyrazolyl H B17NO₂ Cl CH(Me)CH₂Me H B18 MeO Cl CH₃ H B19 Cl H CH₃ H B20 Cl Cl CH₃ H B21H F CH₃ H B22 F H CH₃ H B23 NO₂ Cl Ph H B24 NO₂ Cl propyl H B25 NO₂ Clcyclopropyl H B26 F F CH₃ H B27 NO₂ H CH₃ H B28 H H CH₃ H B29 I F CH₃ HB30 H Cl CH₃ H B31 NO₂ F CH₃ H B32 Cl F CH₃ H B35 CN F CH₂OH H C1CON-morpholine amide F H H C2 CONHCH₂CH₂OH F H H C4 NH₂ Cl CH₃ H C6 NH₂Cl i-Pr H C7 AcNH Cl CH₃ H C8 AcryloylNH Cl CH₃ H C9 MsNH Cl CH₃ H C10NO₂ Cl CONH₂ H C12 NO₂ Cl CONHNH₂ H C13 NO₂ Cl CHO H C14 NO₂ Cl CH₂OH HC16 NO₂ Cl CH₂OMe H C17 NO₂ Cl CH═CH₂ H C18 NO₂ Cl CN H C19 CONH₂ F CH₃H D1 NO₂ m-NO₂** H H D2 NO₂ CF₃ CH₃ H D3 Me₂NSO₂NH Cl CH₃ H D4ClCH₂NHSO₂NH Cl CH₃ H D5 morpholinylSO₂NH Cl CH₃ H D6 NO₂ Cl2-thiophenyl H D7 NO₂ Cl 2-furanyl H D8 NO₂ Cl 2-(3-Me)-thiophenyl H D9NO₂ Cl 3-pyridinyl H D10 NO₂ Cl 4-pyridinyl H D11 NO₂ Cl p-MeSPh H D12NO₂ Cl p-CF₃OPh H D13 NO₂ Cl o,m- H methylenedioxy-Ph D14 NO₂ Clp-OH-o-MeOPh H D15 NO₂ Cl 3-thiophenyl H D16 NO₂ Cl p-Ph—Ph H D17 NO₂ Clm-NO₂Ph H D18 NO₂ H cyclopropyl H D50 CONH₂ F H H D51 CON-morpholineamide F CH₃ H D52 CONHCH₂CH₂OH F CH₃ H D53 CONHCH₂CH₂—N— F CH₃ Hmorpholinyl Unless otherwise indicated. **Position 3′.

In the remainder of the tables, the position of the substituted R¹, R²,R³ and R⁴ are as provided in Table IA above.

TABLE IB Inhibition of Cdk2 - IC₅₀ Range 1-9.99 μM Compound Number R¹ R²R³ R⁴ A6 Cl H H H A7 Cl F H H A9 H H H H A10 H F H H A11 F F H H A14CH₃SO₂ H H H A18 CO₂CH₃ H H H A19 I F H H B2 NO₂ Cl CO₂Et H B5 NO₂ ClCH₂CH₂Ph H B8 NO₂ Cl CH₂Ph H B11 NO₂ Cl CH₂-iPr H B33 I H CH₃ H C3CON(CH₂CH₂OH)₂ F H H C5 NH₂ Cl H H C11 NO₂ Cl CONMe₂ H D19 NO₂ Cl2-benzofuranyl H D20 NO₂ Cl 2-indoylyl H D21 NO₂ Cl 2-N—Me-pyrrolyl HD22 CO₂H F H H D23 NO₂ Cl m-OH—Ph H D24 NO₂ Cl p-MePh H D25 NO₂ Clm-CNPh H D26 NO₂ Cl 2-(5-Me)-thiophenyl H D27 NO₂ H 3-pyridinyl H D28NO₂ Cl p-Me2NPh H D29 NO₂ Cl o-CNPh H D30 NO₂ Cl m-MePh H D31 NO₂ Clm-EtO-Ph H D32 NO₂ Cl 2-(5-Et)-furanyl H D33 NO₂ Cl 2-naphthyl H D34 NO₂H 2-imidazolyl H D35 CO₂Na H H H D37 NO₂ Cl o-MePh H

TABLE IC Inhibition of Cdk2 - IC₅₀ Range 10-30 μM Compound Number R¹ R²R³ R4 A4 Cl Cl H H D38 NO₂ Cl 1-oxadiazolyl H D39 NO₂ Cl o-NO₂Ph H D40NO₂ Cl o-CF₃Ph H D41 NO₂ Cl m-CF₃Ph H D42 NO₂ Cl o-MeOPh H D43 NO₂ Cl4-N-pyrrolylPh H D44 NO₂ Cl m-PhOPh H D45 NO₂ H m,p-methylenedioxy-Ph HD46 NO₂ H m,p-ethylenedioxy-Ph H D47 NO₂ H o-F—Ph HCell-Based Assays

The estrogen receptor negative epithelial breast carcinoma line(MDA-MB-435) was purchased from American Type Cell Culture Collection(ATCC; Rockville, Md.) and was grown in the medium recommended by ATCC.For analysis of the effect of the test compounds on growth of thesecells, the cells were plated at 2000 cells per well in a 96-well tissueculture plate, and were incubated overnight at 37° C. with 5% CO₂. Thenext day, the test compounds were dissolved in 100% dimethyl sulfoxide(DMSO) to yield a 10 mM stock solution. Each compound was diluted withsterile medium to 1 mM in a sufficient quantity to yield a finalconcentration of 120 μM. The compounds were then serially diluted inmedium with 1.2% DMSO. One-fourth final volume of the diluted compoundswas transferred to 96 well plates. Test compounds were assayed induplicate. DMSO was added to a row of “control cells” such that thefinal concentration of DMSO in each well was 0.3%. Wells to which nocells were added served as the “blank.” Wells to which no inhibitor wasadded served as “no inhibitor control”. The plates were returned to theincubator, and 5 days post addition of test compound, were analyzed asdescribed below.

3-(4,5-Dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide(thiazolyl blue; MTT) was added to each well to yield a finalconcentration of 1 mg/mL. The plates were then incubated at 37° C. for 3hours. The plates were centrifuged at 1000 rpm for 5 minutes prior toaspiration of the MTT-containing medium. The MTT-containing medium wasthen removed and 100 μL 100% ethanol was added to each well to dissolvethe resulting formazan metabolite. To ensure complete dissolution,plates were shaken for 15 minutes at room temperature. Absorbencies wereread in a microtiter plate reader (Molecular Dynamics) at a wavelengthof 570 nm with a 650 nm reference. Percent inhibition was calculated bysubtracting the absorbance of the blank (no cell) wells from all wells,then subtracting the division of the average absorbance of each testduplicate by the average of the controls from 1.00. Inhibitoryconcentrations (IC₅₀) were determined from the linear regression of aplot of the logarithm of the concentration versus the percentinhibition.

The results of the foregoing MDA-MB-435 cell-based assay are set forthin Tables IIA-IIC below.

TABLE IIA Antiproliferative Activity of MDA-MB435 (breast) Assay - IC₅₀Range 0.01-1 μM Compound Number R¹ R² R³ R⁴ B3 NO₂ Cl CH₃ H B4 NO₂ ClCH₂CH₃ H B6 NO₂ Cl i-Pr H B7 CN F CH₃ H B22 F H CH₃ H B25 NO₂ Clcyclopropyl H B29 NO₂ H CH₃ H B31 NO₂ F CH₃ H B35 CN F CH₂OH H C4 NH₂ ClCH₃ H C7 AcNH Cl CH₃ H C8 AcryloylNH Cl CH₃ H C9 MsNH Cl CH₃ H C13 NO₂Cl CHO H C14 NO₂ Cl CH₂OH H C17 NO₂ Cl CH═CH₂ H D3 Me₂NSO₂NH Cl CH₃ H

TABLE IIB Antiproliferative Activity of MDA-MB435 (breast) Assay - IC₅₀Range 1.1-9.99 μM Compound Number R¹ R² R³ R⁴ A15 CN F H H B9 CO₂Et FCH₃ H B10 NO₂ Cl 5-(4-Me)-pyrazolyl H B12 NO₂ Cl CF₃ H B14 NO₂ Cl4-imidazolyl H B16 NO₂ Cl 3-pyrazolyl H B18 MeO Cl CH₃ H B19 Cl H CH₃ HB20 Cl Cl CH₃ H B21 H F CH₃ H B30 H Cl CH₃ H C6 NH₂ Cl i-Pr H C16 NO₂ ClCH₂OMe H D4 ClCH₂NHSO₂NH Cl CH₃ H D5 morpholinylSO₂NH Cl CH₃ H D51CON-morpholine amide F CH₃ H D52 CONHCH₂CH₂OH F CH₃ H D53 CONHCH₂CH₂—N—F CH₃ H morpholinyl

TABLE IIC Antiproliferative Activity of MDA-MB435 (breast) Assay - IC₅₀Range 10-30 μM Compound Number R¹ R² R³ R⁴ A5 NO₂ Cl H H A13 NO₂ F H HB2 NO₂ Cl CO₂Et H B5 NO₂ Cl CH₂CH₂Ph H B8 NO₂ Cl CH₂Ph H B13 NO₂ Cl1-thiazolyl H B15 NO₂ Cl 2-pyrazolyl H B24 NO₂ Cl Propyl H C5 NH₂ Cl H HC10 NO₂ Cl CONH₂ H C15 NO₂ Cl CH₂NMe₂ H C18 NO₂ Cl CN H D38 NO₂ Cl1-oxadiazolyl H

The colon adenocarcinoma line SW480 and the colon carcinoma line HCT-116also were obtained from the ATCC and were tested according to the sameprotocol provided above for MDA-MB-435 cell based assay with thefollowing modifications. Cell line SW480 was plated at 1000 cells perwell and analyzed at 6 days post addition of the test compound. Cellline HCT-116 was plated at 1000 cells per well and analyzed at 4 dayspost addition of test compound.

The results of the foregoing SW480 (colon) and HCT-116 (colon) basedassays are set forth below in Tables IIIA-IIIC and IVA-IVC,respectively.

TABLE IIIA Antiproliferative Activity SW480 (colon) Assay - IC₅₀ Range0.01-1 μM Compound Number R¹ R² R³ R⁴ B3 NO₂ Cl CH₃ H B4 NO₂ Cl CH₂CH₃ HB6 NO₂ Cl i-Pr H B7 CN F CH₃ H B10 NO₂ Cl 5-(4-Me)-pyrazolyl H B21 H FCH₃ H B26 F F CH₃ H B27 NO₂ H CH₃ H B31 NO₂ F CH₃ H B35 CN F CH₂OH H C1CON-morpholine amide F H H C4 NH₂ Cl CH₃ H C7 AcNH Cl CH₃ H C8AcryloylNH Cl CH₃ H C9 MsNH Cl CH₃ H C14 NO₂ Cl CH₂OH H C19 CONH₂ F CH₃H D2 NO₂ CF₃ CH₃ H D51 CON-morpholine amide F CH₃ H D52 CONHCH₂CH₂OH FCH₃ H D53 CONHCH₂CH₂—N— F CH₃ H morpholinyl

TABLE IIIB Antiproliferative Activity SW480 (colon) Assay - IC₅₀ Range1.1-9.99 μM Compound Number R¹ R² R³ R⁴ A5 NO₂ Cl H H A13 NO₂ F H H A15CN F H H B1 NO₂ Cl 2-pyrrolyl H B9 CO₂Et F CH₃ H B18 MeO Cl CH₃ H B19 ClH CH₃ H B20 Cl Cl CH₃ H B22 F H CH₃ H B25 NO₂ Cl Cyclopropyl H B29 I FCH₃ H B30 H Cl CH₃ H B32 Cl F CH₃ H D3 Me₂NSO₂NH Cl CH₃ H D4ClCH₂NHSO₂NH Cl CH₃ H D5 morpholinylSO₂NH Cl CH₃ H D50 CONH₂ F H H

TABLE IIIC Antiproliferative Activity SW480 (colon) Assay - IC₅₀ Range10-30 μM Compound Number R¹ R² R³ R⁴ A9 H H H H A10 H F H H A11 F F H HA21 H Cl H H B5 NO₂ Cl CH₂CH₂Ph H B8 NO₂ Cl CH₂Ph H B23 NO₂ Cl Ph H B24NO₂ Cl Propyl H B33 I H CH₃ H C5 NH₂ Cl H H C12 NO₂ Cl CONHNH₂ H D6 NO₂Cl 2-thiophenyl H D7 NO₂ Cl 2-furanyl H D9 NO₂ Cl 3-pyridinyl H D10 NO₂Cl 4-pyridinyl H D20 NO₂ Cl 2-indoylyl H B34 Br H CH₃ H D36 NO₂-9-NO₂ ClH H D37 NO₂ Cl o-MePh H D40 NO₂ Cl o-CF₃Ph H D48 NO₂ Cl 1-naphthyl H

TABLE IVA Antiproliferative Activity HCT 116 (colon) Assay - IC₅₀ Range0.01-1 μM Compound Number R¹ R² R³ R⁴ B3 NO₂ Cl CH₃ H B4 NO₂ Cl CH₂CH₃ H

TABLE IVB Antiproliferative Activity HCT 116 (colon) Assay - IC₅₀ Range1.1-9.99 μM Compound Number R¹ R² R³ R⁴ A15 CN F H H B1  NO₂ Cl2-pyrrolyl H B6  NO₂ Cl i-Pr H B7  CN F CH₃ H B9  CO₂Et F CH₃ H B10 NO₂Cl 5-(4-Me)-pyrazolyl H B25 NO₂ Cl Cyclopropyl H C12 NO₂ Cl CONHNH₂ HD50 CONH₂ F H H

TABLE IVC Antiproliferative Activity HCT 116 (colon) Assay - IC₅₀ Range10-30 μM Compound Number R¹ R² R³ R⁴ A5  NO₂ Cl H H A9  H H H H A10 H FH H A13 NO₂ F H H A14 CH₃SO₂ H H H A16 NO₂ H H H A21 H Cl H H B5  NO₂ ClCH₂CH₂Ph H B8  NO₂ Cl CH₂Ph H B23 NO₂ Cl Ph H B24 NO₂ Cl Propyl H C1 CON-morpholine amide F H H C2  CONHCH₂CH₂OH F H H C5  NH₂ Cl H H D6  NO₂Cl 2-thiophenyl H D7  NO₂ Cl 2-furanyl H D8  NO₂ Cl 2-(3-Me)-thiophenylH D9  NO₂ Cl 3-pyridinyl H D10 NO₂ Cl 4-pyridinyl H D11 NO₂ Cl p-MeSPh HD12 NO₂ Cl p-CF₃OPh H D13 NO₂ Cl o,m- H methylenedioxy-Ph D14 NO₂ Clp-OH-o-MeOPh H D18 NO₂ H cyclopropyl H D19 NO₂ Cl 2-benzofuranyl H D20NO₂ Cl 2-indoylyl H D36 NO₂-9-NO₂ Cl H H D37 NO₂ Cl o-MePh H D41 NO₂ Clm-CF₃Ph H D43 NO₂ Cl 4-N-pyrrolylPh H D48 NO₂ Cl 1-naphthyl H D49 NO₂ Cl4-isoquinolinyl H

H Ingredients Mg/Tablet I Compound 1* 5 25 100 250 500 750 J AnhydrousLactose 103 83 35 19 38 57 K Croscarmellose Sodium 6 6 8 16 32 48 LPovidone K30 5 5 6 12 24 36 M Magnesium Stearate 1 1 1 3 6 9 N TotalWeight 120 120 150 300 600 900 *Compound 1 represents a compound of theinvention.

Manufacturing Procedure:

-   1. Mix Items 1, 2 and 3 in a suitable mixer for 15 minutes.-   2. Granulate the powder mix from Step 1 with 20% Povidone K30    Solution (Item 4).-   3. Dry the granulation from Step 2 at 50° C.-   4. Pass the granulation from Step 3 through a suitable milling    equipment.-   5. Add the Item 5 to the milled granulation Step 4 and mix for 3    minutes.-   6. Compress the granulation from Step 5 on a suitable press.

Example 6 Capsule Formulation

O Ingredients mg/Capsule P Compound 1* 5 25 100 250 500 Q AnhydrousLactose 159 123 148 — — R Corn Starch 25 35 40 35 70 S Talc 10 15 10 1224 T Magnesium Stearate 1 2 2 3 6 U Total Fill Weight 200 200 300 300600 *Compound 1 represents a compound of the invention.Manufacturing Procedure:

-   1. Mix Items 1, 2 and 3 in a suitable mixer for 15 minutes.-   2. Add Items 4 & 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

Example 7 Injection Solution/Emulsion Preparation

Item Ingredient mg/mL 1 Compound 1*   1 mg 2 PEG 400 10-50 mg 3 Lecithin20-50 mg 4 Soy Oil  1-5 mg 5 Glycerol  8-12 mg 6 Water q.s.   1 mL*Compound 1 represents a compound of the invention.

Manufacturing Procedure:

-   1. Dissolve item 1 in item 2.-   2. dd items 3, 4 and 5 to item 6 and mix until dispersed, then    homogenize.-   3. Add the solution from step 1 to the mixture from step 2 and    homogenize until the dispersion is translucent.-   4. terile filter through a 0.2 um filter and fill into vials.

Example 8 Injection Solution/Emulsion Preparation

Item Ingredient mg/mL 1 Compound 1*    1 mg 2 Glycofurol 10-50 mg 3Lecithin 20-50 mg 4 Soy Oil  1-5 mg 5 Glycerol  8-12 mg 6 Water q.s. 1mL *Compound 1 represents a compound of the invention.Manufacturing Procedure:

-   1. Dissolve item 1 in item 2.-   2. Add items 3, 4 and 5 to item 6 and mix until dispersed, then    homogenize.-   3. Add the solution from step 1 to the mixture from step 2 and    homogenize until the dispersion is translucent.-   4. Sterile filter through a 0.2 um filter and fill into vials.

While the invention has been illustrated by reference to specific andpreferred embodiments, those skilled in the art will understand thatvariations and modifications may be made through routine experimentationand practice of the invention. Thus, the invention is intended not to belimited by the foregoing description, but to be defined by the appendedclaims and their equivalents.

1. A compound of formula

wherein: R¹ is selected from the group consisting of —H, —NO₂, —CN,-halogen, -lower alkyl which is straight-chained and which optionallymay be substituted by the group consisting of —OH and halogen, —OR⁵,—R⁶—OR⁷, —COOR⁷, —CONR⁸R⁹, —NR¹⁰R¹¹, —NHCOR¹², and —NHSO₂R¹³; R² and R⁴are each independently selected from the group consisting of —H,-halogen, —NO₂, —CF₃, and —straight chained lower alkyl; R⁵ is selectedfrom lower alkyl which optionally may be substituted by halogen; R⁶ isselected from —(CH₂)₁₋₆—; R⁷ is selected from the group consisting of —Hand lower alkyl; R⁸ and R⁹ are each independently selected from thegroup consisting of —H and -lower alkyl which itself optionally may besubstituted by —OH and —NH₂; alternatively, R⁸ and R⁹ may form a 5- or6-membered heterocycle which optionally may be substituted by the groupconsisting of —OH, —NH₂, and lower alkyl; R¹⁰, R¹¹ and R¹² are eachindependently selected from the group consisting of —H and lower alkyl;R¹³ is selected from the group consisting of lower alkyl whichoptionally may be substituted by the group consisting of halogen and—NR¹⁴R¹⁵; and R¹⁴ and R¹⁵ are each independently selected from the groupconsisting of —H and lower alkyl which optionally may be substitutedhalogen, or alternatively, —NR¹⁴R¹⁵ is a heterocycle.
 2. The compound ofclaim 1, wherein R¹ is on position 7 and is selected from the groupconsisting of —H, —NO₂, —CN, halogen and lower alkyl.
 3. The compound ofclaim 1, wherein R¹ is on position 8 and is selected from the groupconsisting of —H, —NO₂, —CN, halogen and lower alkyl.
 4. A compound offormula

wherein: R¹ is selected from the group consisting of —H, —NO₂, —CN,-halogen, -lower alkyl which is straight-chained and which optionallymay be substituted by the group consisting of —OH and halogen, —OR⁵,—R⁶—OR⁷, —COOR⁷, —CONR⁸R⁹, —NR¹⁰R¹¹, —NHCOR¹², and —NHSO₂R¹³; R² and R⁴are each independently selected from the group consisting of —H,-halogen, —NO₂, —CF₃, and -straight chained lower alkyl; R³ is selectedfrom the group consisting of —H, -lower alkyl which optionally may besubstituted by —OH, —OR⁹, F, and aryl, -cycloalkyl, -aryl, -heterocycle,-heteroaryl, —COOR⁷ —CN, -alkenyl, —CONR⁸R⁹, and -alkynyl; R⁵ isselected from lower alkyl which optionally may be substituted byhalogen; R⁶ is selected from —(CH₂)₁₋₆—; R⁷ is selected from the groupconsisting of —H and lower alkyl; R⁸ and R⁹ are each independentlyselected from the group consisting of —H and —lower alkyl which itselfoptionally may be substituted by —OH and —NH₂; alternatively, R⁸ and R⁹may form a 5- or 6-membered heterocycle which optionally may besubstituted by the group consisting of —OH, —NH₂, and lower alkyl; R¹⁰,R¹¹ and R¹² are each independently selected from the group consisting of—H and lower alkyl; R¹³ is selected from the group consisting of loweralkyl which optionally may be substituted by the group consisting ofhalogen and —NR¹⁴R¹⁵; and R¹⁴ and R¹⁵ are each independently selectedfrom the group consisting of —H and lower alkyl which optionally may besubstituted halogen, or alternatively, —NR¹⁴R¹⁵ is a heterocycle.
 5. Thecompound of claim 4 wherein R¹ is on position 7 and is selected from thegroup consisting of —H, —NO₂, —CN, halogen and lower alkyl.
 6. Thecompound of claim 4, wherein R¹ is on position 8 and is selected fromthe group consisting of —H, —NO₂, —CN, halogen and lower alkyl.
 7. Thecompound of claim 5 wherein R¹ is methyl or ethyl.
 8. The compound ofclaim 6 wherein R¹ is methyl or ethyl.
 9. The compound of claim 1,wherein R² is on the 2′ position and is selected from the groupconsisting of H and halogen.
 10. The compound of claim 4 wherein R³ isselected from the group consisting of lower alkyl, cycloalkyl,heterocycle, and heteroaryl.
 11. The compound of claim 10 wherein R³ isselected from the group consisting of methyl and ethyl.
 12. The compoundof claim 10 wherein R³ is C₃-C₅ cycloalkyl.
 13. The compound of claim 4wherein R⁴ is at the 4′ position and is selected from the groupconsisting of H and halogen.
 14. The compound of claim 4 wherein R⁵ isselected from the group consisting of methyl and ethyl, each of whichoptionally may be substituted by halogen.
 15. The compound of claim 14wherein R⁵ is trifluoromethyl.
 16. The compound of claim 4 wherein R⁷ isselected from the group consisting of —H, methyl and ethyl.
 17. Thecompound of claim 4 wherein R⁸ is selected from the group consisting ofH, methyl, ethyl, and hydroxyethyl.
 18. The compound of claim 4 whereinR⁹ is selected from the group consisting of H, methyl, ethyl, andhydroxyethyl.
 19. The compound of claim 4 wherein R⁸ and R⁹ form aheterocycle.
 20. The compound of claim 19 wherein R⁸ and R⁹ form a6-membered heterocycle that includes two heteroatoms.
 21. The compoundof claim 20 wherein the heteroatoms are independently selected from Oand N.
 22. The compound of claim 4 wherein R¹⁰, R¹¹ and R¹² are eachindependently selected from the group consisting of —H, methyl andethyl.
 23. The compound of claim 4 wherein R¹³ is lower alkyl whichoptionally may be substituted by halogen.
 24. The compound of claim 23wherein R¹³ is selected from the group consisting of methyl, ethyl andtrifluoromethyl.
 25. The compound of claim 4 wherein R¹⁴ and R¹⁵ areeach independently selected from the group consisting of H, methyl, andethyl, or alternatively, the group NR¹⁴R¹⁵ is a heterocycle.
 26. Thecompound of claim 25 wherein the heterocycle is a 3-7 membered ring thatincludes at least one nitrogen atom.